Macrophages are key cells that direct innate immune responses to pathogens that are detected through specific pattern recognition receptors. We will analyze the transcriptomes of macrophages infected with Burkholderia pseudomallei and determine the transcription factors and signaling molecules that are activated in response to infection. By examining macrophages deficient for central signaling molecules, we will ascribe specific transcriptional clusters to TLR signaling (MyD88/Trif null cells), NLR signaling (Rip2 or caspase 1 null cells) or type I interferon signaling (IFNaRI null cells). In parallel, we will determine the transcriptional response to specific bacterial virulence factors or PAMPs in B. pseudomallei, including the type III and VI secretion systems, actin polymerization, flagellin and quorum sensing. We will computationally identify specific transcription factors that are activated and identify the compendium of genes that each of three transcription factor regulates. Finally, we will validate the transcriptional networks that are defined and determine their effect on B. pseudomallei infection in vivo and in vitro.